title: Involvement of heparan sulfate in the renoprotective effects of imidapril, an angiotensin-converting enzyme inhibitor, in diabetic db/db mice.
abstract: We investigated the renoprotective effects of imidapril hydrochloride ((-)-(4 S)-3-[(2 S)-2-[[(1 S)-1-ethoxycarbonyl-3-phenylpropyl] amino] propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril), an angiotensin-converting enzyme inhibitor, in a diabetic animal model. We used BKS.Cg-+Lepr(db)/+Lepr(db) (db/db) mice, a genetic animal model of obese type 2 diabetes. Diabetic db/db mice suffered from glomerular hyperfiltration, albuminuria and hypoalbuminemia. Oral administration of 5 mg/kg/day of imidapril for 3 weeks suppressed renal hyperfiltration, reduced albuminuria and normalized hypoalbuminemia. Imidapril did not influence body weights, blood pressure or blood glucose concentrations in db/db mice. Urinary excretion of heparan sulfate (HS) in non-treated 11-week-old db/db mice was significantly lower than that in age-matched non-diabetic db/+m mice. HS is a component of HS proteoglycans, which are present in glomerular basement membranes and glycocalyx of cell surfaces. Reduced urinary HS excretion indicated glomerular HS loss in db/db mice. Imidapril increased urinary excretion of HS to concentrations observed in db/+m mice, indicating that imidapril prevented the loss of renal HS. These results suggest that imidapril ameliorates renal hyperfiltration and loss of renal contents of HS. Improvement of filtration function and maintenance of HS, which is an important structural component of glomeruli, may contribute to renoprotective effects of imidapril.
authors.affiliation: Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corporation , Kawagishi, Toda-shi, Saitama , Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Yoneda
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Ueta
authors.forename: Masaaki
authors.initials: M
authors.lastname: Nagasaki
authors.forename: Kenji
authors.initials: K
authors.lastname: Arakawa
mesh_terms: D000284:Administration, Oral; D000419:Albuminuria / Q000150:complications / Q000188:drug therapy; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D006497:Heparan Sulfate / Q000008:administration & dosage*; D006801:Humans; D034141:Hypoalbuminemia / Q000150:complications / Q000188:drug therapy; D048289:Imidazolidines / Q000008:administration & dosage*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D009765:Obesity / Q000150:complications / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001786:Blood Glucose; D006497:Heparan Sulfate; D048289:Imidazolidines; C065166:imidapril